3.2.0 Interferons

3.2.0 Interferons

Interferons are types of naturally-occurring proteins produced by cells of the immune system. Three classes of interferons have currently
been identified:Alfa (also known as alpha), beta and gamma. Each class has different effects, though their activities overlap.

Together, the interferons direct the immune system's attack on viruses, bacteria, tumours and other foreign substances that may invade the
body.

Current standard HCV treatment combines ribavirin with pegylated interferon, a type of interferon with a large polyethylene glycol molecule
attached to it. [See 3.2.2] When combined, these two drugs drastically improve the response rates.

Virtually all interferons used in HCV treatment today are obtained from recombinant bacterial sources (bacteria that have had slight man-made
DNA modifications). In general, genetic material from human leucocytes is spliced into the genetic material of bacteria, and the bacteria are
allowed to reproduce and grow. The inserted genetic material causes the bacteria to produce interferon. Recombinant interferons of one type or
another have been used to fight HCV since 1991.

A number of new therapies for hepatitis C are emerging in clinical practice. Trials are being done with combinations of pegylated interferon
and other substances, with re-treatment, with different types and brands of interferon, with longer-term therapy, and with long-term maintenance
therapy.

3.2.1 Interferon Monotherapy

At one time, interferon alone was considered standard therapy. It is now used alone only when the patienthas some condition, such as
anemia or a heart problem, that doesn’t permit the use of ribavirin.

3.2.2 Pegylated Interferon

Polyethylene glycol (PEG) is a substance with a high molecular weight that is easily excreted in the urine, due to being soluble in water.
PEG attachment to interferon alpha leads to a longer half-life (the amount of time for given concentration of the drug in the body to drop by
half). NOTE: Drugs may be metabolized or just excreted. Half life covers both methods.

Comparisons of the two available pegylated interferons, Peg-Intron and Pegasys have been made. The two substances differ basically in the
size of the molecule involved, (40 kilodalton for Pegasys, 12 kilodalton for Peg-Intron), Pegasys has a longer half life and there are studies
that say one or the other are more effective.

3.2.2a Pegylated Intron A (Peg-Intron A)

PEG-Intron A is a modified form of Merck’s Intron A (interferon alpha-2b, recombinant), developed by Enzon,Inc., to have longer-acting
properties than non-pegylated interferon. It is usually given along with ribavirin in the treatment of HCV. About 52% of genotype 1 patients
achieve SVR on this combination therapy. 85% of genotype 2 and and 78% of genotype 3 patients achieve SVR. (
www.hivandhepatitis.com/2005icr/aasld/docs/111405j.html Nov 2005)

3.2.3a Consensus Interferon (CIFN, Infergen, Interferon Alfacon-1)

Interferon alfacon-1 is a recombinant non-naturally occurring type-I interferon. The 166-amino acid sequence of Interferon alfacon-1 was
derived by scanning the sequences of several natural interferon alpha subtypes and assigning the most frequently observed amino acid in each
corresponding position. The drug has undergone extensive clinical testing for treating hepatitis C, cirrhosis, and a form of cancer. (
www.valeant.com )

Preliminary results were released at the AASLD conference in November 2007 from a trial studying 400 nonresponders, 92% with genotype 1. The
patients took either CIFN (Consensus IFN) at 9 ug daily for 16 weeks, or CIFN 27 ug daily for 4 weeks, followed by 12 weeks of CIFN 18 ug daily.
Both treatment groups then continued with CIFN at 9 ug daily plus weight-based RBV for 32 to 56 weeks, depending on the first PCR-negative
result, to ensure 48 weeks of PCR-negative treatment. The sustained viral response rates (SVR) were 16% for non-responders to Peg-IFN a-2b
(Pegetron) and 23% for non-responders to Peg-IFN a-2a (Pegasys). The results were better with the higher dose, but the higher dose was less
tolerable during the high dose induction period. Drop out rates were the same in both groups. CIFN daily dosing/induction therapy followed by
RBV combination therapy shows promising response rates in non-responders. Peg-IFN a-2a nonresponders especially seem to benefit from daily CIFN
retreatment.(
www.hcvadvocate.org/news/reports/AASLD2007/Abstracts/Tuesday%20posters.htm Nov 2007 Topic 1306)

3.2.3c Omega Interferon

Omega and alpha interferons are very similar: they are both type-1 interferons, bind to the same receptor and their basic chemical make-ups
are 70% the same. The omega interferon comes from a different source, which gives it greater stability at body temperature for prolonged periods
Intarcia has acquired rights to a delivery system that may permit the administration of omega interferon for weeks or months with a single
administration in the form of a device implanted under the skin. ( www.intarcia.com )

In Phase I and two Phase II trials involving more than 200 infected patients, Intarcia has shown omega interferon given by injection to be
effective against HCV. The first Phase II trial with 90 patients showed that even in genotype-1 cases, omega interferon alone produced Early
Viral Response (EVR) rates that compare favourably to alpha IFN.In the second Phase II trial, 102 genotype 1 patients were enrolled and
separated randomly into different arms. 67 patients received omega plus ribavirin. 35 received omega alone. The EVR were 84% for combination
therapy and 60% for monotherapy ( www.intarcia.com/FinalDDW2007Phase2.htm May
21, 2007 and www.intarcia.com/press/intarPR1115.htm )

3.2.3d Albuferon

Albuferon, developed by Human Genome Sciences and Novartis under license from ZLB Behring, is a long-acting interferon that is fused to a
human albumin protein. Several studies suggest that Albuferon may offer efficacy at least comparable to the peginterferon alpha-2a/2b, with half
the injections and possibly fewer side effects.

Genotype 1 Patients: researchers, presented data from a Phase IIb study evaluating albumin interferon in 458 treatment-naïve genotype 1
patients in 8 countries. They were assigned to receive 1 of 3 doses of injected albumin interferon, either 900 or 1200 mcg once every 2 weeks or
1200 mcg once every 4 weeks, or standard therapy.

Conclusion: The researchers concluded the data suggest that “the Q2W albumin interferon regimens may offer at least comparable or increased
efficacy, with an improved dosing schedule and the potential for fewer side effects compared with Q1W pegylated interferon.“

Genotype 2 or 3 Patients: In a second study, researchers studied albumin IFN in 43 naïve genotype 2 or 3 patients in a multicenter,
open-label Phase II trial. Some received injections of 1500 mcg every 2 weeks or every 4 weeks, plus 800 mg/day ribavirin. Treatment lasted 24
weeks, the same as standard therapy for these genotypes.

3.2.3e Belerofon

Nautilus Biotech is developing a set of improved IFN-alpha molecules with a longer half-life, without using pegylation technology. The
product is called BELEROFON® and it is being developed as an oral medication. ( www.nautilusbiotech.com and
www.nautilusbiotech.com/news100507.html 14 May, 2007)

There has been no news on the Internet since its Phase I clinical trial in 2007.

3.2.3f Maxygen

Maxygen (R7025) is a pegylated IFN alpha product candidate which may be a therapy for non-responders to current drugs. Roche initiated a
Phase Ia clinical trial in New Zealand for the lead MAXY-alpha candidate at the end of 2006.

As a result, the drug was put on hold, pending further investigation, due to decreased effectiveness of the drug and to the emergence of
antibodies to the drug in some patients. Its development was terminated as of November 25, 2007.(
www.maxygen.com/products-hep.php Nov 2007 and
www.pharmatimes.com Nov 27, 2007 )

3.2.3g Locteron (BLX-883)

Locteron is Biolex Therapeutics’ lead product. Locteron is a type of IFN alpha that uses a technology called OctoPlus to release the drug in
a controlled manner. Locteron is the most advanced drug being developed that uses that technology. OctoPlus gave Biolex exclusive commercial
rights to the technology in October 2008. Locteron has not been approved for sale yet.

In October 2010, results of Phase IIb SELECT-2 clinical trials were published, demonstrating that the drug was tolerable for up to 60 weeks,
and the findings were presented at the AASLD 2010 conference. The trial consisted of 48 weeks of treatment with 3 different doses of the drug,
and results at 12 weeks posttreatment (SVR12) showed sustained benefits equal to or better than PegIntron and because of the OctoPlus
controlled-release technology, the patients received doses only once every 2 weeks, rather than once weekly, as done with PEG-Intron and
Pegasys. Flu-like symptoms associated with interferon were reduced, so fewer analgesic medications were used. Depression rates were lower, as
were adverse events. The company believes that a more tolerable interferon will reduce side-effects for patients taking the new combination
treatments.(
http://www.clinicaloptions.com )

3.2.3h PEG-interferon lambda (IL-29)

ZymoGenetics’ PEG-interferon lambda (IL-29) signals through a receptor with a different pattern than type-I interferons alpha, beta and omega
and has broad anti-viral activity. This native human protein is induced by the body in response to viral infections, and uses a different
receptor than that used by the interferons we with Hep C know.

Bristol-Myers Squibb and ZymoGenetics have pegylated the product. It is a type III IFN, and it is hoped it will be less toxic than the types
presently used in HCV therapy. A small Phase Ib, ongoing trial enrolled genotype 1 treatment relapsers, taking pegIFN Lambda weekly or every 2
weeks, with or without ribavirin, for 4 weeks. The drug was well-tolerated and the effects were comparable to standard therapy. Half of the
patients treated weekly with IFN alone had an undetectable viral load at 4 weeks (RVR). 80% had a viral load below 1000 IU/L. Weekly dosing was
more effective, with all patients achieving a viral load drop of over 2 log10. (EASL 2009)

ZymoGenetics and Bristol-Myers Squibb presented week 12 results from their phase IIa trial of pegIFN lambda plus RBV, which compared the drug
to standard treatment using pegIFN alfa-2a/RBV, in hopes of finding a more tolerable interferon.The trial involved 55 treatment-naïve patients,
and stratified them according to C/C or non-C/C before randomizing them. Patients taking pegIFN lambda experienced virologic responses equal to
or better than standard therapy in GT1 and GT4 patients, but lower responses in GT2 and GT3 patients. Up to half of patients with non-C/C
genotype had undetectable virus at week 12. Adverse events were noted in fewer than 25% of pegIFN lambda patients. The events were mild to
moderate, with no deaths and no need to lower the dose. More results were expected in 2011.(www.clinicaloptions.com)

Results through week 12 for the Phase IIb EMERGE trial of pegIFN Lambda vs. pegIFN Alfa-2a in 42 genotype 1, 2 and 3 treatment-naïve patients
with compensated cirrhosis were presented. Both drugs were combined with RBV.

Lambda was well tolerated, and needed fewer dose reductions of IFN or RBV. There were fewer incidences of blood abnormalities like anemia or
neutropenia. Response rates were similar. In the branch of the trial with 526 non-cirrhotic patients, Lambda showed a better viral response
compared to pegIFN alfa-2a through week 12, also with fewer dose reductions. Response rates were better in GT2/3 than GT1. The non-cirrhotic
patients responded better than the cirrhotic patients. IFN Lambda is produced naturally by the body. The trial is being run principally by
ZymoGenetics and Bristol-Myers Squibb.( http://www.natap.org/2011/AASLD/AASLD38.htm
)

3.2.3i Glycoferon

Alios BioPharma is working on improving pegylated interferon, by changing the amino acid sequence, and introducing glycosylation sites into
the protein, and minimizing any disadvantages of the drug, without losing its potency, which is especially important, since non-responders are
unlikely to respond to re-treatment. The pegylation process reduces the potency of the IFN, unfortunately. It appears that the resulting product
is 3 logs10 more potent than Peg-IFN alpha 2a. Previous non-responders may, however, have more positive results if a more potent IFN is included
in the combination treatment. It is hoped that clinical trials for non-responders will begin in about 18 months.(www.natap.org/2008/EASL/EASL46.htm )

3.2.3j IFN alpha-2b XL (Medusa IFN)

Medusa’s IFN alpha-2b XL is a slow-release human IFN which was shown to be safe in a Phase I study. A Phase Ib study was done to prove the
antiviral activity of two doses of the drug, given weekly, to 23 naïve patients (most with genotype 3) compared to Peg-IFN alpha 2b. The first
dose showed similar activity in both drugs. The second dose, however, showed a 0.57 log reduction compared to only a 0.21 log reduction with the
Peg-INF alpha 2b. The new drug was better tolerated. (www.flamel.com/techAndProd/flamel-ifn-easl.pdf
April 25, 2008)

3.2.3k ViraferonPeg

This drug produced by Merck is now approved in India for relapsers and non-responders, as a result of their EPIC3 clinical study showing that
certain non-responders even to prior pegylated treatments have successful re-treatment results. 1,336 patients were treated in the study. Of
those who had undetectable virus at week 12 (EVR), which according to the rules of the study, qualified them to continue treatment for a total
of 48 weeks, 57% achieved SVR in the non-pegylated arm and 47% in the pegylated arm. (EASL 2009)

3.2.3l Oral Interferon

Amarillo Biosciences’s development partner CytoPharm has announced approval to begin a Phase II clinical trial of 165 chronic hepatitis C
patients in Taiwan. The study will try to reduce the relapse rate of patients who have completed standard therapy, and will treat them with one
of two doses of oral interferon lozenges or placebo. The company plans to announce the results in late 2010.(www.reuters.com/article/pressRelease/idUS186683+13-Feb-2009+MW20090213
Feb 13 2009 andhcvadvocate.org July 1, 2009)